1. Field of the Invention
This invention relates to compositions for enhancement of delivery of oxubutynin, antimuscarinic and spasmolytic drugs, by administration via the nasal route to treat patients suffering from overactive bladder with symptoms of urinary urgency, frequency or urge incontinence. The invention is also directed to methods of treatment thereof, and methods of preparation thereof.
2. Description of the Related Art
U.S. Pat. No. 6,039,967 to Ottoboni, describes an intravesical drug delivery system for placement of oxybutynin into the bladder through the urethra.
U.S. Pat. No. 5,840,754 to Guittar, describes the administration of a controlled-release dosage form tablet comprising oxybutynin to lessen the incidence of side effects.
U.S. Pat. No. 5,736,577 to Aberg, describes the use of optically pure (S)-oxybutynin for treating urinary incontinence.
U.S. Pat. No. 5,674,895 to Guittard, describes a rate-controlled tablet dosage form of oxybutynin.
U.S. Pat. No. 5,500,222 to Lee, describes the transdermal administration of oxybutynin together with a suitable permeation enhancer.
Oxybutynin, [Benzeneacetic acid, a-cyclohexyl-a-hydroxy-4-(diethylamino)-2-butynyl ester], a tertiary amine with antimuscarinic, spasmolytic and local anesthetic properties, is currently used for the treatment of overactive bladder with symptoms of urinary urgency, frequency or urge incontinence due to detrusor instability or detrusor hyperreflexia. Oxybutynin is currently marketed in the United States under the trade names Ditropan and Ditropan XL as an oral dosage form (Physician ""s Desk Reference, pp 507, 54th Edition, 2000).
After oral administration of oxybutynin, low systemic bioavailability ( less than 6%) is observed because of extensive first-pass metabolism (Douchamps et al., Eur. J. Clin. Pharmacol. 35:515, 1988). Oxybutynin is metabolized in the liver and it has been suggested that the metabolite N-desethyloxybutynin, is pharmacologically active (Lindeke et al., Biomed. Mass. Spec. 8: 506, 1981; Aaitonen et al., Acta Pharmacol. Toxicol. 55: 100, 1984) and is associated with the systemic side effects following oral treatment with oxybutynin (Buyse et al., J. Urology 160:892, 1998). Measurements of oxybutynin and N-desethyloxybutynin plasma levels after oral administration of oxybutynin resulted in a considerably larger (5 to 11 fold) concentration of the metabolite compared with the parent compound (Hughes et al, Xenobiotica 22: 859, 1992). Functional and receptor binding experiments have also demonstrated that N-desethyloxybutynin has similar anticholinergic activity to the parent compound on isolated human bladder and parotid gland (Waldeck et al., J. Urology 157: 1093, 1997). Despite the clinical success of intravesical oxybutynin, the exact mechanism of action remains unknown. As systemic side effects were generally absent when the drug was applied intravesically (Buyse et al., J. Urology 160:892, 1998), it has been suggested that oxybutynin was not absorbed into the blood stream and that its efficacy resulted from a profound local effect alone. Measurements of plasma levels of oxybutynin after intravesical and oral administration revealed extensive inter-individual variations, but clearly there was substantial absorption of the drug after intravesical application and therefore its effect on detrusor muscle was believed to be mainly systemic due to its absorption (Madersbacher and Jilg, Paraplegia 29: 84, 1991; Massad et al., J. Urology 148: 595, 1992; Madersbacher and Knoll, Eur. J. Urology 28: 340, 1995). Although no measurements of circulating metabolites were performed in these studies, it has been speculated that a difference in metabolite concentration, due to reduced first pass metabolism, could explain the difference in systemic side effects. Alternatively, there might be a different metabolism after oral administration, compared with intravesical instillation, due to enzymatic reactions in the alimentary tract. In contrast to the promising clinical results of intravesical oxybutynin therapy, patient withdrawal was significant (up to 65%) in several studies, mainly due to practical inconvenience and, to a lesser extent, untoward effects (Kasabian et al., J. Urol. 151: 944, 1994; Connor et al., J. Urol. 151: 1045, 1994; Palmer et al., J. Urol. 157:638, 1997). Hernandez et al. concluded that the only disadvantage to intravesical therapy appeared to be variable long-term patient compliance (Hernandez et al., J. Urol. 152:1582, 1994).
Among the adverse effects of oxybutynin following oral administration include dry mouth, constipation, diarrhea, nausea, vomiting, somnolence, dizziness, headache pain, insomnia, tachycardia (Physician ""s Desk Reference, pp 507, 54th Edition, 2000; Drug Information, AHFS 99: pp. 3164, 1999). In clinical studies, adverse reactions requiring discontinuance of oxybutynin therapy (5 mg 3 times daily) occurred in about 20% of patients.
Therefore, in view of the aforementioned deficiencies attendant with prior art compositions and methods of oxybutynin administration, it should be apparent that there still exists a need in the art for a safe and convenient composition and method for administering oxybutynin to patients at safe and effective doses. To the best of applicants"" knowledge, nasal administration of oxybutynin is unknown and completely unsuggested by the art.
While nasal administration has become an accepted route of administration, the following disclosures limit that mode of delivery to specific drugs described. Moreover, it has been observed that many therapeutic agents cannot be usefully administered by this unusual route. Consequently, nasal administration remains a technique for which applicability is far from universal and the results unpredictable.
Accordingly, a major object of the present invention is to provide a composition and method for the safe, convenient and effective way of administering the useful drugs oxybutynin to a patient in need of such treatment. The method comprises intranasal administration of an effective amount of oxybutynin for the treatment of overactive bladder with symptoms of urinary urgency, frequency or urge incontinence and other disorders.
Nasal drug administration serves as an alternative route of drug administration. It has been shown that most drugs administered nasally produce plasma levels similar to those following intravenous administration (Hussain, et al., J. Pharm. Sci. 69:1240, 1980; Bawarshi-Nassar et al., J. Pharm. Pharmacol 41: 214, 1989; Hussa in, et al., J. Pharm. Sci. 68: 1196, 1979). The nasal delivery route is a very useful method of drug administration, which frequently improves drug bioavailability by direct absorption into the circulation avoiding hepatic first-pass metabolism and destruction in the gastrointestinal tract following oral delivery of drug (Chien, et al., Marcel Dekker, New York, 1989.).
The objective of the present inventions is to improve oxybutynin bioavailability by administering oxybutynin via the nasal route in order to reduce the dose required for its beneficial effect. Intranasal oxybutynin delivery will improve drug bioavailability by direct absorption into the circulation avoiding extensive hepatic first-pass metabolism which significantly lowers the plasma concentrations of oxybutynin administered orally. Therefore, small doses of oxybutynin can be administered which will results in fewer side effects, and the drug will be more tolerable and more effective in treating patients suffering from overactive bladder with symptoms of urinary urgency, frequency or urge incontinence and other disorders described above. Additionally, as oxybutynin is heavily metabolized by the liver, administration by the nasal route will help to reduce drugxe2x80x94drug interactions with other drugs that are also extensively metabolized by the liver.
Nasal administration of oxybutynin would be expected by the Applicants to increase oxybutynin blood levels with a concomitant decrease in blood levels of their major metabolites N-desethyloxybutynin. This expected increase by Applicant in drug concentration ratio of unchanged oxybutynin to metabolite in the systemic circulation is even more significant in light of studies which indicate the association of the major metabolites N-desethyloxybutynin with significant side effects.
In addition, nasal oxybutynin administration is easy and convenient. Furthermore, in many situations it has already been shown that the onset and extent of drug delivery after intranasal administration is comparable to the same drug and dose being given intravenously. Therefore, intranasal delivery of drug for treatment of overactive bladder with symptoms of urinary urgency such as oxybutynin could be used in those situations where a rapid or intermittent drug effect is desired.
In certain embodiments, the invention is directed to a method of providing oxybutynin therapy to a patient in need thereof comprising intranasally administering an effective amount of oxybutynin or a pharmaceutically acceptable salt thereof to said patient and compositions thereof. Preferably, the oxubutynin is administered with a pharmaceutically acceptable carrier which can be in the form of, e.g. a solution, suspension, gel, ointment, lotion, semi-solid, vaporizable carrier, a powder and combination thereof. In certain embodiments, the carrier can provide a sustained release of the drug.
In certain embodiments, the invention is directed to a method of reducing side effects associated with oxybutynin therapy comprising administering a therapeutically effective amount of oxybutynin intranasally, the intranasal administration reducing side effects associated with the oral administration of an equivalent dose of oxybutynin. In certain embodiments, the intranasal administration reduces side effects by reducing the formation of the N-desethyl metabolite of oxybutynin as compared to an equivalent dose of oral oxybutynin.
In certain embodiments, the ratio of the plasma concentration of the desmethyl metabolite of oxybutynin after said intranasal administration to the plasma concentration of the N-desethyl metabolite of oxybutynin after the oral administration is less than about 1:5, less than about 1:10 or less than about 1:20.
In certain embodiments, the ratio of the plasma concentration of the N-desethyl metabolite said nasal administration to the plasma concentration of oxybutynin is less than about 2:1, less than about 1:1, less than about 0.75:1, or less than about 0.55:1.
In certain embodiments, the bioavailability of the of the intranasal oxybutynin is increased as compared to an equivalent dose of oral oxybutynin. In preferred embodiments, the ratio of the AUC after intranasal oxybutynin to AUC of oxybutynin after an equivalent dose of oral oxybutynin is at least 2:1 or at least 4:1, and preferably at least 8:1 or at least 10:1. In certain embodiments, the ratio is based on the absolute AUC and other embodiments the AUC is measured at 2 hours after administration. The ratios are also based on the oral oxybutynin being administered as a solution or a tablet.
With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention is further explained in the following detailed description of the preferred embodiments of the invention and in the appended claims.